Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis
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KIF1A gene encodes the kinesin 1a protein, an axonal motor protein working in cargo transport along neurites. Variants in KIF1A were identified in different forms of neurodegenerative diseases with dominant and recessive inheritance. Homozygous recessive mutations were found in the hereditary sensory and autonomic neuropathy type 2, HSAN2 and in a recessive subtype of hereditary spastic paraparesis, SPG30. De novo heterozygous dominant variants were found both in a dominant form of SPG30 (AD-SPG30) with one single family reported and in patients with different forms of progressive neurodegenerative diseases. We report the results of a genetic screening of 192 HSP patients, with the identification of four heterozygous variants in KIF1A in four cases, two of whom with family history for the disease. Three of the four variants fall within the motor domain, a frequent target for variants related to the AD-SPG30 subtype. The fourth variant falls downstream the motor domain in a region lacking any functional domain. The KIF1A-related patients show clinical pictures overlapping the known AD-SPG30 phenotype including pure and complicated forms with few differences. Of note, one of the families, originating from the Sicily island, carries the same variant p.S69L detected in the first AD-SPG30 family of Finnish origin reported; differently from the first one, the latter family shows a wide intra-familial phenotype variability. Overall, these data reveal a very low frequency of the AD-SPG30 subtype while confirming the presence of amino acid residues in the motor domain representing preferential targets for mutations, thereby supporting their functional relevance in kinesin 1a activity.
KeywordsNGS-targeted resequencing Spastic paraparesis KIF1A Dominant inheritance
The authors wish to thanks the patients and their families for participation to this work and all referring clinicians for collaboration. This work was supported by the Italian Ministry of health under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases” Grant NEUROLIPID and Grant No. 2015 and 5xMille.
Compliance with ethical standards
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study. We have not included any details that might disclose the identity of the subjects in the study.
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